The large number of patients with chronic pain constitutes a major human tragedy, a significant economic burden and is a reflection of our inadequate understanding of pain mechanisms. This program project addresses the neurobiology of pain and opioid analgesia. The emphasis of the program is to promote interaction, active collaboration and clinically significant research. This goal will be achieved through biweekly research conferences and sharing of equipment and techniques, antibodies, genetically manipulated mice. The anatomical core will serve four of the five projects by providing confocal and electron microscopic support. Using a combination of anatomical, electrophysiological and pharmacological techniques, Dr. Basbaum will investigate a unique population of non-peptidergic primary afferent nociceptors that terminate in the inner substantia gelatinosa. He will exploit this finding that serotonin acting at the 5HT3 receptor selectivity activates these afferents. Dr. Fields will elucidate the neural pathways that mediate the affective- motivational aspect of pain. He will employ formalin as the noxious stimulus and conditioned place aversion as the behavioral test. Drs. Fields and Basbaum will collaborate to investigate the contributions of both substance P-containing and non-peptidergic primary afferents to aversiveness. Fields will study the role in aversion of the spinomesencephalic and spinothalamic tracts and the anterior cingulate, somatosensory, and dysgranular insular corteces. He will collaborate with Dr. Ralston to anatomically define the nociceptive relay from medial thalamus to anterior cingulate cortex. Dr. Ralston will continue his studies of ultrastructural changes in central somatosensory pathways following peripheral nerve injury. Levine, using behavioral methods and both in vivo primary afferent and in vitro dorsal root ganglion recordings, will study the cellular mechanisms of pain and hyperalgesia in rodent experimental diabetic neuropathy. Drs. Ralston and Levine will collaborate on ultrastructural studies of peripheral nerve and of dorsal horn reorganization in this neuropathy. In normal human volunteers and patients Drs. Rowbotham and Fields will investigate two important clinical issues related to opioid analgesia. First, are there opioid insensitive pains? Second, does analgesic tolerance develop with prolonged use of opioids in patients with chronic pain? These issues will be studied using a new method (heat followed by capsaicin) to produce opioid responsive pain and cutaneous hyperalgesia. The analgesic effect of opioidscan then be studied in the same patient for both clinical and experimental pain.